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At least 541 records · Page 30Linked to original sources

PubMed2003

Cytokine gene expression in a mouse model: the first instillations with viable bacillus Calmette-Guerin determine the succeeding Th1 response.

PURPOSE: Bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer is immune dependent and activation of a Th1 immune response is probably required for clinical efficacy. Given the empirical approach to improving BCG therapy we investigated in a mouse model the consequences of modifications in BCG therapy with regard to Th1 and Th2 cytokine responses in the bladder. These studies may provide a rationale for possible modifications of the established clinical treatment protocol. MATERIALS AND METHODS: The dynamics of Th1 (interferon-gamma, interleukin [IL]-2, IL-12p40 and tumor necrosis factor-alpha) and Th2 (IL-10 and IL-4) cytokine responses during and after 6 once weekly intravesical BCG instillations in mice was determined by a semiquantitative reverse transcriptase-polymerase chain reaction based method. RESULTS: During 6 weekly BCG instillations a dose and time dependent induction of the various Th1 as well as Th2 cytokines was observed. The response pattern was comparable to urinary cytokine induction patterns in patients. Electrocauterization prior to BCG instillations led to lower and more variable levels of cytokine polymerase chain reaction products compared with noncauterization. Lowering the dose of BCG seemed to affect the Th1 cytokine response most, whereas the Th2 response was less influenced by dilution of the BCG preparation. Six instillations with nonviable BCG induced Th2 but failed to induce Th1 cytokines, which may explain the necessity of BCG viability for antitumor activity. However, when mice were first treated 3 times with viable BCG and subsequently received 3 instillations with killed BCG, the Th1 and Th2 cytokine pattern was comparable to the standard 6-week regimen with viable BCG. CONCLUSIONS: The model seems an appropriate one in which to investigate changes in Th1 and Th2 cytokine gene expression levels in bladders resulting from modifications in intravesical BCG treatment. It was possible to induce a local Th1 cytokine response with nonviable BCG provided that local sensitization to BCG antigens had occurred during preceding instillations with a viable BCG preparation. Whether such an approach could decrease BCG therapy toxicity, while maintaining antitumor efficacy, remains to be further investigated in patients.

Administration, Intravesical↗

PubMed1995

Neuronal transients.

A recent letter to Nature (Vaadia et al. Nature, Lond. 373, 515-518 (1995)) presented compelling results concerning neuronal interactions in monkey cortex. Vaadia et al. made two fundamental points: (i) it is possible that cortical function is mediated by dynamic modulation of coherent firing among neurons; and (ii) these time-dependent changes in correlations can emerge without modulation of firing rates. These observations have severe implications for models of neural coding and empirical approaches that are based on firing rates (e.g. neuroimaging). This communication presents a simpler explanation for the results presented in Vaadia et al., by noting they are consistent with the correlated expression of stereotyped neuronal transients following (or preceding) a salient event. This re-formulation is important because: (i) correlations measured in terms of transients are not time-dependent, allowing prevailing models of neural coding to be 'reinstated'; and (ii) it suggests a powerful analysis based on singular value decomposition of firing rates.

Animals↗

PubMed1999

Model-based development of neuroprosthesis for paraplegic patients.

In paraplegic patients with upper motor neuron lesions the signal path from the central nervous system to the muscles is interrupted. Functional electrical stimulation applied to the lower motor neurons can replace the lacking signals. A so-called neuroprosthesis may be used to restore motor function in paraplegic patients on the basis of functional electrical stimulation. However, the control of multiple joints is difficult due to the complexity, nonlinearity, and time-variance of the system involved. Furthermore, effects such as muscle fatigue, spasticity, and limited force in the stimulated muscle further complicate the control task. Mathematical models of the human musculoskeletal system can support the development of neuroprosthesis. In this article a detailed overview of the existing work in the literature is given and two examples developed by the author are presented that give an insight into model-based development of neuroprosthesis for paraplegic patients. It is shown that modelling the musculoskeletal system can provide better understanding of muscular force production and movement coordination principles. Models can also be used to design and test stimulation patterns and feedback control strategies. Additionally, model components can be implemented in a controller to improve control performance. Eventually, the use of musculoskeletal models for neuroprosthesis design may help to avoid internal disturbances such as fatigue and optimize muscular force output. Furthermore, better controller quality can be obtained than in previous empirical approaches. In addition, the number of experimental tests to be performed with human subjects can be reduced. It is concluded that mathematical models play an increasing role in the development of reliable closed-loop controlled, lower extremity neuroprostheses.

Electric Stimulation Therapy↗

PubMed2003

Dressing the mind properly for the game.

Game theory as a theoretical and empirical approach to interaction has spread from economics to psychology, political science, sociology and biology. Numerous social interactions-foraging, talking, trusting, coordinating, competing-can be formally represented in a game with specific rules and strategies. These same interactions seem to rely on an interweaving of mental selves, but an effective strategy need not depend on explicit strategizing and higher mental capabilities, as less sentient creatures or even lines of software can play similar games. Human players are distinct because we are less consistent and our choices respond to elements of the setting that appear to be strategically insignificant. Recent analyses of this variable response have yielded a number of insights into the mental approach of human players: we often mentalize, but not always; we are endowed with social preferences; we distinguish among various types of opponents; we manifest different personalities; we are often guided by security concerns; and our strategic sophistication is usually modest.

Brain↗

PubMed2006

Avipoxvirus phylogenetics: identification of a PCR length polymorphism that discriminates between the two major clades.

Avipoxvirus infections have been observed in an extensive range of wild, captive and domesticated avian hosts, yet little is known about the genome diversity and host-range specificity of the causative agent(s). Genome-sequence data are largely restricted to Fowlpox virus (FWPV) and Canarypox virus (CNPV), which have been sequenced completely, showing considerable divergence between them. It is therefore proving difficult, by empirical approaches, to identify pan-genus, avipoxvirus-specific oligonucleotide probes for PCR and sequencing to support phylogenetic studies. A previous preliminary study used the fpv167 locus, which encodes orthologues of vaccinia virus core protein P4b (A3). PCR per se did not discriminate between viruses, but restriction-enzyme or sequence analysis indicated that the avipoxviruses clustered either with FWPV or with CNPV. Here, further study of the P4b locus demonstrated a third cluster, from psittacine birds. A newly identified locus, flanking fpv140 (orthologue of vaccinia virus H3L), confirms the taxonomic structure. This locus is particularly useful in that viruses from the fowlpox-like and canarypox-like clusters can be discriminated by PCR on the basis of fragment size, whilst sequence comparison allows discrimination for the first time between Pigeonpox virus and Turkeypox virus. Except within the psittacines, virus and avian host taxonomies do not show tight correlation, with viruses from the same species located in very different clades. Nor are all the existing recognized avipoxvirus species, defined primarily by avian host species (such as CNPV and Sparrowpox virus), resolved within the present structure.

Amino Acid Sequence↗

PubMed2000

Reflection anisotropy spectroscopy: A new probe for the solid-liquid interface

Introducing reflection anisotropy spectroscopy (RAS) as a new probe for solid-liquid interfaces, we present results for the Au(110)/electrolyte interface which serves as a model system. We demonstrate that RAS is sensitive to surface phase transitions, step morphology, and electronic surface states. Using an empirical approach, the RA spectra are reproduced and features are identified which reflect the known character of the bias voltage driven (2x1) to (1x1) phase transition. RAS is established as an experimental technique to probe the electronic structure of solid-liquid interfaces in real time to study a wide range of interface properties.

Journal Article↗

PubMed2003

Lysosomal cysteine proteases (cathepsins): promising drug targets.

Papain-like lysosomal cysteine proteases are processive and digestive enzymes expressed in organisms from bacteria to humans. Their ubiquity alone makes them potential drug targets, with the assumption that appropriate specificities may be achieved. These enzymes have rather short active-site clefts, comprising three well defined substrate-binding subsites (S2, S1 and S1') and additionally have comparatively broad binding areas (S4, S3, S2', S3'). This geometry distinguishes them from other protease classes, such as serine and aspartic proteases, with six and eight substrate-binding sites, respectively. Exopeptidases (cathepsins B, C, H and X), in contrast to endopeptidases (such as cathepsins L, S, V and F), possess structural features that facilitate binding of N- and C-terminal groups of substrates in the active-site cleft. Other than a clear preference for free chain termini in the case of exopeptidases, the substrate-binding sites exhibit no strict specificities. Instead, their subsite preferences arise more from specific exclusions of substrate type. This presents a challenge for the design of inhibitors to target a specific cathepsin: only the cumulative effect of an assembly of inhibitor fragments can produce the desired result. The small number of papain-like lysosomal cysteine proteases (11 human enzymes are known) and the small number of substrate-binding sites calls for a innovative and empirical approach.

Amino Acid Sequence↗

PubMed1995

Computational studies of transthoracic and transvenous defibrillation in a detailed 3-D human thorax model.

A method for constructing and solving detailed patient-specific 3-D finite element models of the human thorax is presented for use in defibrillation studies. The method utilizes the patient's own X-ray CT scan and a simplified meshing scheme to quickly and efficiently generate a model typically composed of approximately 400,000 elements. A parameter sensitivity study on one human thorax model to examine the effects of variation in assigned tissue resistivity values, level of anatomical detail included in the model, and number of CT slices used to produce the model is presented. Of the seven tissue types examined, the average left ventricular (LV) myocardial voltage gradient was most sensitive to the values of myocardial and blood resistivity. Incorrectly simplifying the model, for example modeling the heart as a homogeneous structure by ignoring the blood in the chambers, caused the average LV myocardial voltage gradient to increase by 12%. The sensitivity of the model to variations in electrode size and position was also examined. Small changes (< 2.0 cm) in electrode position caused average LV myocardial voltage gradient values to increase by up to 12%. We conclude that patient-specific 3-D finite element modeling of human thoracic electric fields is feasible and may reduce the empiric approach to insertion of implantable defibrillators and improve transthoracic defibrillation techniques.

Computer Simulation↗

PubMed2006

Towards a nursing minimum data set for Ireland: making Irish nursing visible.

AIM: The aim of this study was to identify patient problems, nursing interventions and nursing outcomes to be included in a nursing minimum data set for Ireland. BACKGROUND: In 2002, a research programme funded by the Irish Health Research Board, was established to develop and test a nursing minimum data set to capture the nursing contribution to patient care in Ireland. A nursing minimum data set is comprised of the smallest number of information items required to capture the range of patient problems, nursing interventions and nursing outcomes recorded by nurses on a regular basis. Nursing minimum data sets have been developed in several countries for a range of applications such as workforce planning, financing nursing care, examining patient profiles and forecasting trends in nursing diagnoses. METHOD: Eleven focus groups were conducted with 59 registered general nurses to explore their conceptualizations of patient problems, nursing interventions and nursing outcomes. In addition, data relating to nurses' recordings of patient problems, nursing interventions and nursing outcomes were collected from a sample of 45 sets nursing records. The research took place between January 2003 and April 2004. FINDINGS: A range of patient problems, nursing interventions and outcomes were identified that were similar to those found in existing nursing minimum data sets. However, several new items and categories of items were also identified, justifying the empirical approach taken to generate the initial list of items. Data from nursing records supported several points raised in focus groups and also highlighted some inconsistencies between nurses' perceptions and recordings of what they do. CONCLUSION: Our research identified several new types of indirect interventions and managing/organizing activities in addition to items found in existing nursing minimum data sets. The importance of these aspects of the nursing contribution to patient care will be tested further in the development of the Irish nursing minimum data set.

Adult↗

PubMed1982

The tracer method of curriculum analysis: identifying changes in oncology subject matter in medicine.

Changes occurring in oncology subject matter in an undergraduate medical curriculum over a 5-year period were documented using the tracer method of curriculum analysis. The tracer method is an empirical approach somewhat analogous to tracing one thread through a tapestry, as a way of following a subject matter interwoven throughout a curriculum. Advantages of the method can be to bring particular material to the attention of teaching staff and students, to facilitate more efficient instruction, and to introduce peer review of educational material.

Curriculum↗

PubMed2005

Genetic quality and sexual selection: an integrated framework for good genes and compatible genes.

Why are females so choosy when it comes to mating? This question has puzzled and marveled evolutionary and behavioral ecologists for decades. In mating systems in which males provide direct benefits to the female or her offspring, such as food or shelter, the answer seems straightforward--females should prefer to mate with males that are able to provide more resources. The answer is less clear in other mating systems in which males provide no resources (other than sperm) to females. Theoretical models that account for the evolution of mate choice in such nonresource-based mating systems require that females obtain a genetic benefit through increased offspring fitness from their choice. Empirical studies of nonresource-based mating systems that are characterized by strong female choice for males with elaborate sexual traits (like the large tail of peacocks) suggest that additive genetic benefits can explain only a small percentage of the variation in fitness. Other research on genetic benefits has examined nonadditive effects as another source of genetic variation in fitness and a potential benefit to female mate choice. In this paper, we review the sexual selection literature on genetic quality to address five objectives. First, we attempt to provide an integrated framework for discussing genetic quality. We propose that the term 'good gene' be used exclusively to refer to additive genetic variation in fitness, 'compatible gene' be used to refer to nonadditive genetic variation in fitness, and 'genetic quality' be defined as the sum of the two effects. Second, we review empirical approaches used to calculate the effect size of genetic quality and discuss these approaches in the context of measuring benefits from good genes, compatible genes and both types of genes. Third, we discuss biological mechanisms for acquiring and promoting offspring genetic quality and categorize these into three stages during breeding: (i) precopulatory (mate choice); (ii) postcopulatory, prefertilization (sperm utilization); and (iii) postcopulatory, postfertilization (differential investment). Fourth, we present a verbal model of the effect of good genes sexual selection and compatible genes sexual selection on population genetic variation in fitness, and discuss the potential trade-offs that might exist between mate choice for good genes and mate choice for compatible genes. Fifth, we discuss some future directions for research on genetic quality and sexual selection.

Animals↗

PubMed2001

Impact of (bio)chemical and physical procedures on food allergen stability.

A variety of methods have been used to attempt to decrease the allergenicity of food products, with highly variable success. Limited knowledge of allergen and epitope structures and the factors governing their stability may explain this, and the ensuing need for an empirical approach. A combined effort from a processing and genomics-based approach may open up new ways to improve the quality of foods from an allergenic perspective. Based on structural knowledge, a suitable approach can be chosen that is, for instance, heat stable but protease sensitive; protease resistant but not heat stable; easy to extract; easy to mask because the epitope is exactly on a crosslink site; a molecular probe design that allows screening of germplasm collections.

Allergens↗

PubMed1981

Studies on hydrogen bonds. Part IV. Proposed working criteria for assessing qualitative strength of hydrogen bonds.

The data obtained in the earlier parts of this series for the donor and acceptor end parameters of N-H...O and O-H...O hydrogen bonds have been utilised to obtain a qualitative working criterion to classify the hydrogen bonds into three categories: "very good" (VG), "moderately good" (MG) and weak (W). The general distribution curves for all the four parameters are found to be nearly of the Gaussian type. Assuming that the VG hydrogen bonds lie between O and +/- 1 sigma, MG hydrogen bonds between +/- 1 sigma and +/- 2 sigma, W hydrogen bonds beyond +/- 2 sigma (where sigma is the standard deviation), suitable cut-off limits for classifying the hydrogen bonds in the three categories have been derived. These limits are used to get VG and MG ranges for the four parameters 1 and theta (at the donor end) and zeta and xi (at the acceptor end). The qualitative strength of a hydrogen bond is decided by the cumulative application of the criteria to all the four parameters. The criterion has been further applied to some practical examples in conformation studies such as alpha-helix and can be used for obtaining suitable location of hydrogen atoms to form good hydrogen bonds. An empirical approach to the energy of hydrogen bonds in the three categories has also been presented.

Chemical Phenomena↗

PubMedDate not supplied

Recent progress in pharmacological therapy of male subfertility--a review.

A review of pharmacological therapy in male infertility shows that apart from specific therapy with gonadotropins in hypogonadotropic hypogonadism, treatment in normogonadotropic idiopathic oligozoospermia and asthenozoospermia is still empirical and often unsuccessful. Modern therapy is based on three pharmacological groups of compounds: gonadotropins, androgens and kininogenases, the latter releasing pharmacologic active kinin peptides from kininogen. In addition, antiestrogens and gonadotropin-releasing hormones seem to be promising agents for the near future. The use of antibiotics is of great importance in the therapy of male genital tract infections which often to a reduced fertility. Several other drugs (amino acids, psychopharmaceuticals, spasmolytic agents, trijodothyronine, glucocorticoids, vitamins) seem to be suitable in individuals cases, but in greater group of patients these agents do not improve fertility. Using the mentioned hormonal and nonhormonal pharmacological agents considerable progress can be demonstrated in the therapy of male infertility. However, before initiating any therapy it is important to exclude patients whose cause of infertility is untreatable or those who require surgery. Finally, it is hoped that additional progress in treatment of male infertility will soon be made possible by further improvement of fundamental research in andrology. Especially important is the development of better criteria for selection of patients for any form of therapy in order to make more specific and less empirical approaches for treatment of male infertility available.

Anti-Infective Agents↗

PubMed1991

Privacy and disclosure in medical genetics examined in an ethics of care.

The progress of genetic knowledge magnifies existing ethical problems in medical genetics. Among the most troubling types of problems -- for medicine, patients, and the larger society -- are those of privacy and disclosure. Examples of the range of problems involving privacy and disclosure are: 1) disclosure of false paternity to an unsuspecting husband; 2) disclosure of a patient's genetic make-up to his or her unknowing spouse; 3) disclosure of information, against a patient's wishes, to relatives at genetic risk; 4) disclosure of ambiguous test results; 5) disclosure of adventitious nonmedical information, e.g., fetal sex; and 6) disclosure to institutional third parties, such as employers and insurers....

Attitude↗

PubMed1995

Weighting health states and strong evaluation.

The problem of public consultation over the allocation of health care resources is addressed by considering the role that quality of life measures, such as QALYs and the Nottingham Health Profile, could play. Such measures are typically grounded in social surveys, and as such may reflect public preferences for health care priorities. Using Charles Taylor's concepts of "weak" and "strong" evaluation, it is suggested that current quality of life measures are inadequate, insofar as they typically presuppose that survey respondents are mere "weak evaluators", who express only inarticulate preferences. Respondents may, conversely, be understood as strong evaluators, with deeper visions of human nature and the good life informing their health preferences. Space is then created for such respondents to be asked to defend their preferences, and so be encouraged to reflect critically and publicly on the beliefs and prejudices that ground their view of health care priorities.

Community Participation↗

PubMed1995

Women, ectogenesis and ethical theory.

The nature of two influential theories on the moral status of abortion logically commits them to welcoming the advent of ectogenesis (the gestation of human beings outside the womb) as a solution to the abortion conflict. However, qualitative research into women's response to ectogenesis reveals that both women in favour and women opposed to abortion rights reject the technology on surprisingly similar grounds. The abortion framework which led women to reject ectogenesis as an ethical resolution to unwanted pregnancy is contrasted with the moral framework which shapes formal ethical discussions of abortion. It is argued that the need for ethical relevance requires the views of ethicists to move closer to those of women.

Abortion, Induced↗

PubMed1999

The pharmacologic basis of antiepileptic drug action.

The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever-growing armentarium of AEDs, necessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action.

Animals↗